Over the past decade, the use of MRI to study multiple sclerosis (MS) has lead to substantial advances in understanding the disease process. Disease activity as detected by new lesions on T2-weighted images or contrast-enhancing lesions on T1-weighted images have established that the level of activity seen on MRI is considerably greater than that seen clinically. Further, MRI has become an important and powerful tool for the assessment of the effect of new experimental therapies in MS. Recent work continues to focus on defining the natural history of the disease using MRI and in examining the effect of experimental treatments on disease activity as measured by MRI. Specifically, recent studies have focused on the following; 1. Defining the natural history of the MS lesion using both conventional imaging as well as advanced imaging techniques including magnetization transfer imaging, proton spectroscopy and measures of T1 hypointensities. 2. Defining the level of new disease activity seen in patients who are early in the relapsing remitting course of the disease? 3. Examining the evidence of involvement of gray matter in the disease process 4. Examining of the effect of new therapies on disease activity in MS as measured by MRI. [unreadable] Serial studies of patients with early, relapsing-remitting MS using contrast enhanced MRI have shown that nearly two thirds of the patients have evidence of active new lesion formation. Studies in the NIB have shown that the evolution of the MS lesion using imaging techniques that measure tissue destruction such as T1 hypointensities and alterations in magnetization transfer ratios is variable suggesting that distinct mechanisms may contribute to lesion progression. Those lesions that enhance for longer than 2 months have a greater chance of developing into a persistent T1 hypointensity indicating tissue damage. This evidence indicates that qualitative differences exist in contrast enhancing lesions. The results indicate that mechanisms of tissue destruction may be, in part distinguished from the events that initiate the lesion. In addition to the studies of the natural history of the acute lesion in MS, the usefulness of T1 hypointensities as an outcome measure in clinical trials has also been examined and the large data collection available in the NDS has been used to estimate sample sizes needed for clinical trials.[unreadable] Recent studies have begun to examine the degree to which MRI can demonstrate tissue damage in either the deep gray matter or the cortex in patients with MS. Pathological studies have indicated that involvement of gray matter is not uncommon although the pathological appearance differs from that in white matter in that there is less inflammation. The demonstration of damage in gray matter using MRI has been largely unsuccessful. Studies in the NDS have now shown that several imaging approaches can be used to reproducibly demonstrate lesions in the cortex. Further, in collaboration with investigators at Harvard School of Medicine, significant thinning of the cortex, especially the prefrontal cortex and motor cortex is seen in patients even those early in the disease process. A correlation with clinical motor function also has been seen indicating that the cortical involvement may by one component of the clinical disability in MS. Damage to deep gray matter has also been demonstrated using regional MTR analysis. In addition diffusion weighted imaging has been used to study involvement of deep gray matter especially the thalamus.[unreadable] Finally, MRI continues to be an important part of clinical trials in the NIB. Studies of daclizumab using contrast enhancing lesions as the primary outcome in patients who have failed conventional therapy with interferon beta have successfully demonstrated the effectiveness of this therapy. A current study is examining the value of the therapy as an initial treatment in a cohort of patients. The findings from theNDS studies have now resulted in multicenter phase II testing the therapy.